Use of picoplatin to treat colorectal cancer

ABSTRACT

The invention provides a method of treatment of colorectal cancer by administration of the anti-cancer platinum drug picoplatin in conjunction with 5-FU and leucovorin in a variety of treatment regimens. Dosages, dosing schedules, and ancillary treatments are described.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/982,841, filed Nov. 5, 2007, now abandoned which application claimsthe priority of U.S. Provisional Patent Applications, Ser. Nos.60/857,066 (filed Nov. 6, 2006), 60/857,725 (filed Nov. 8, 2006),60/877,495 (filed Dec. 28, 2006), 60/889,191 (filed Feb. 9, 2007),60/931,589 (filed May 24, 2007), and 60/983,852 (filed Oct. 30, 2007),which are incorporated by reference herein in their entireties.

BACKGROUND OF THE INVENTION

Colorectal cancer remains the second most common cause of cancer-relateddeath in the United States and a significant cause of cancer-relateddeath in other countries as well.¹ For decades, the only approvedchemotherapeutic drug for treatment of colorectal cancer was5-fluorouracil (5-FU), and it continues to be the backbone of mostfirst-line chemotherapeutic regimens for patients with advanced disease.However, there has been much progress made in treatment of colorectalcancer in the past decade, with the approval of several new therapeuticagents including irinotecan, oxaliplatin, capecitabine, and mostrecently, cetuximab and bevacizumab.^(2,3) Importantly, a variety of newchemotherapeutic regimens utilizing these agents have been devised,which have led to increased response rates and incremental increases inthe time to progression and median survival for patients with advanceddisease.^(2,3) Response rates for 5-FU/leucovorin, irinotecan, andoxaliplatin as single agent therapy have been low (23%, 18%, and 12%,respectively), progression-free survival has been short (median 4.0,4.3, and 4.0 months, respectively), and median survival has also beenshort, approximately (12, 12, and 14.5 months, respectively).⁴ With theintroduction of 5-FU-based combination chemotherapeutic regimens usingirinotecan and oxaliplatin, the response rate has increasedsubstantially, with response rates reported as high as 64% (FOLFOX7),time to progression ranging from 8.9-12.3 months, and median survivalnow approaching approximately 20 months in some reports.²⁻⁴

Unfortunately, however, these newer combination chemotherapy regimens dohave increased toxicity. Regimens containing irinotecan are associatedwith significant diarrhea and other gastrointestinal toxicity, whilethose containing oxaliplatin are associated with neurotoxicity.²⁻¹⁰ Theneurotoxicity observed is of two types: first, a cumulative and oftendose limiting sensory loss with paresthesias that can interfere withfunction and second, a disturbing cold sensitivity that limits patientacceptance of the FOLFOX regimen.⁷⁻¹⁰ Thus a drug of comparable efficacywithout neurotoxicity would be a welcome substitute for oxaliplatin incombination with 5-FU and leucovorin.

Picoplatin is a platinum analogue that has demonstrated synergy with5-FU in vitro in pre-clinical studies and has undergone extensive Phase1 and 2 testing in a variety of cancers.¹¹⁻²² Like other platinumanalogues, picoplatin causes cell death by the formation of covalentcross-links in DNA that interfere with DNA replication andtranscription, leading to cell death. Cisplatin, the first platinumanalogue, was introduced approximately 20 years ago and is still widelyused. The approval of cisplatin was followed by approval of carboplatin,and most recently by that of oxaliplatin.

Treatment with platinum analogues is limited by their toxicity. Whileneurotoxicity and nephrotoxicity are the main dose-limiting toxicities(DLT) observed following cisplatin treatment, myelosuppression is mostsignificant following carboplatin treatment. Carboplatin is known tocause cumulative dose-related toxicity that results in slow bone marrowrecovery. Peripheral neurotoxicity is well documented in patientstreated with oxaliplatin. The unacceptable nephrotoxicity, oto-, andneurotoxicity associated with earlier platinum analogues has not beenreported with picoplatin either in animal studies or in clinicaltrials.^(11, 19-22)

The efficacy of platinum analogues is also limited by several (intrinsicor acquired) mechanisms of resistance, including impaired cellularuptake, intracellular inactivation by thiols [e.g., reducedglutathione], and enhanced DNA repair and/or increased tolerance toplatinum-DNA adducts.²³ Pre-clinical studies indicate that picoplatincan overcome these three mechanisms of resistance. This has beendemonstrated in vitro and by using human ovarian xenograft tumor modelsthat exhibit resistance to cisplatin.¹³⁻¹⁷ Several human ovarian andcolon cell lines with induced resistance to oxaliplatin retainsensitivity to picoplatin.¹⁶⁻¹⁸

In Phase 1 studies, indications of activity were seen in subjects withovarian cancer, non-small cell lung cancer (NSCLC), small cell lungcancer (SCLC), head and neck cancer, renal cell cancer, thymic cancer,pancreatic cancer, stomach cancer, leiomyosarcoma, liver cancer,mesothelioma, and prostate cancers.^(24,25) In Phase 2 studies,indications of efficacy were seen in subjects with ovarian, NSCLC, SCLC,mesothelioma, prostate cancer, and breast cancer.

Picoplatin and processes for making picoplatin and for using picoplatinin treatment are disclosed and claimed in U.S. Pat. Nos. 5,665,771(issued Sep. 9, 1997), and 6,518,428 (issued Feb. 11, 2003), and inPCT/GB0102060, filed May 10, 2001, published as WO2001/087313, which areincorporated herein by reference in their entireties.

Therefore, there is a need for an effective clinical treatment regimenscomprising picoplatin.

SUMMARY OF THE INVENTION

An embodiment of the present invention provides a method of treatment ofcolorectal cancer, comprising administering to a patient afflicted withmetastatic colorectal cancer picoplatin, 5-fluorouracil (5-FU), andleucovorin, wherein 5-FU and leucovorin are administered intravenouslyat least twice at intervals of about 2-6 weeks and the picoplatin isadministered with the leucovorin and 5-FU every other time that thefluorouracil and leucovorin are administered.

Another embodiment of the invention provides a method of treatment ofcolorectal cancer, comprising administering to a patient afflicted withmetastatic colorectal cancer effective amounts of a combination ofpicoplatin, 5-FU and leucovorin, wherein the picoplatin, 5-FU andleucovorin are administered intravenously at least twice at intervals ofabout two weeks, wherein the amount of picoplatin is less than themaximum tolerated dose of picoplatin when administered in saidcombination.

Another embodiment of the invention provides a method of treatment ofcolorectal cancer, comprising administering to a patient afflicted withmetastatic colorectal cancer picoplatin, 5-FU, and leucovorin, wherein5-FU and leucovorin are administered intravenously at intervals of abouttwo weeks, and the picoplatin is administered with the leucovorin and5-FU every time that the fluorouracil and leucovorin are administered,wherein the picoplatin is administered at a dose of about 45-120 mg/m².

In one embodiment of the present method, the patient preferably has notpreviously had systemic treatment, such as chemotherapy, for metastaticdisease. The patient may have, however, received earlier adjuvanttherapy at the time of primary tumor treatment, at least 6 months priorto the present picoplatin treatment.

In another embodiment of the invention, the picoplatin is administeredsubstantially concurrently with the leucovorin and the picoplatin isadministered at every second treatment of the patient with the 5-FU andthe leucovorin, e.g., every four weeks. The leucovorin can beadministered at a dosage of about 250-500 mg/m², preferably at about 400mg/m². The picoplatin is administered at a dosage of about 60-180 mg/m².The 5-FU is administered at a total dosage of about 2500-3000 mg/m². Apreferred treatment cycle for leucovorin and 5-FU is every two weeks,and picoplatin is administered every 4 weeks, e.g., at a low dose ofabout 60-75 mg/m², e.g., 60 mg/m², or at a high dose of about 120-180mg/m², preferably about 120-150 mg/m², e.g. about 150 mg/m².

Therefore, in one embodiment of the invention, the leucovorin, at adosage of 250-500 mg/m², is administered as an about 2 hour infusionconcurrently with the picoplatin, when it is given, wherein thepicoplatin dosage is 120-180 mg/m², e.g., about 150 mg/m²; theadministration of the leucovorin and the picoplatin being followed by a5-FU dosage of about 400 mg/m² as a bolus; the 5-FU dosage beingfollowed by 5-FU at a dosage of 2,400 mg/m², preferably administered asa 46 hour continuous infusion, wherein the leucovorin and 5-FU areprovided to the patient at intervals of two weeks and the leucovorin,picoplatin, and 5-FU are provided to the patient at alternatingintervals of four weeks. In another embodiment, a low dose of picoplatinof about 45-75 mg/m², e.g., about 60-75 mg/m², e.g., about 60 mg/m², isadministered.

In another embodiment of the invention, the leucovorin, at a dosage of400 mg/m², is administered as a 2 hour infusion; the administration ofthe leucovorin being followed by a 5-FU bolus at a dosage of 400 mg/m²;the 5-FU bolus dosage being followed by parenteral 5-FU at a dosage of2,400 mg/m², preferably administered as a 46 hour continuous infusion;the administration of the leucovorin and the 5-FU taking place every twoweeks; wherein every two weeks picoplatin, at a dosage of up to about 50mg/m², e.g., at about 40-50 mg/m², e.g., about 45 mg/m², is administeredconcurrently with the leucovorin, preferably simultaneously. Picoplatindosages of about 45-105 mg/m² can also be administered.

It has unexpectedly been found that, in some cases, the combination oflow doses of picoplatin administered with leucovorin and 5-FU at everytreatment cycle, are as effective as, or more effective than, higherdoses, e.g., the MTD, given at the same intervals, in producing aresponse. The MTD for the 2 week and 4 week picoplatin administrationschedules (see FIGS. 1 and 2) are discussed below. Preferably, suchdoses in the initial treatment are lower or substantially lower than theMTD. Such doses can range from about 40-60 mg/m² of picoplatin every twoweeks, given with leucovorin and followed by 5-FU, as discussed below.

It has surprisingly been found that a total cumulative dose in excess ofabout 900 mg/m² can be tolerated by patients without neuropathy of Grade2 or higher being observed.

As used herein, the term “concurrently” means that the administrationsare simultaneous, overlapping or close enough in time so that the two ormore agents administered are present in vivo in therapeuticallyeffective amounts.

The present method also can comprise administration of an effectiveamount of a 5-HT₃ receptor antagonist, as an anti-emetic.

The present invention also provides a method comprising administeringpicoplatin in a dosage form comprising an isotonic solution comprisingwater, a tonicity adjuster, and about 0.5 mg/mL dissolved picoplatin.The dosage form can also comprise an effective amount of dissolved ordispersed 5-FU and/or leucovorin in accord with the doses disclosedherein. The dosage form also does not contain a preservative orbacteriostatic agent. An appropriate volume of the dosage form can beadministered to achieve a desired therapeutic dose.

The dosage form also can comprise a first container comprising thepicoplatin solution and a second container comprising a solution ofleucovorin. The two containers can further comprise means tosimultaneously administer the contents to a patient, e.g., thecontainers can be plastic intravenous bags that can be independentlyconnected to a single intravenous tube so that the content of eachcontainer can be simultaneously administered to the patient, e.g., via aY-link. These containers can be packaged together with instructionsregarding their end-use, e.g., in a kit.

Picoplatin (SP-4-3) (cis-aminedichloro(2-methylpyridine)Pt(II)), anduseful prodrugs and analogs thereof are disclosed in U.S. Pat. Nos.5,665,771; 6,518,428; 6,413,953 and PCT/GB/01/02060.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 (Phase 1) and 2 (Phase 2) depict a summary of the studytreatments. Phase 1 (Dose Escalation; FIG. 1): Picoplatin: over 2 hrs atassigned dose and schedule; LV: 400 mg/m² over 2 hrs (concurrent withpicoplatin); 5-FU: 400 mg/m² bolus and then 2400 mg/m² over 46 hrs; allsubjects continue cycles every two weeks until progression orwithdrawal. ^(a)Picoplatin: over 2 hours 150 mg/m²; oxaliplatin: 85mg/m², over 2 hours; LV: 400 mg/m² over 2 hours (concurrent withpicoplatin when given or oxaliplatin) followed by 5-FU: 400 mg/m² bolusand then 2400 mg/m² over 46 hours. All subjects continue cycles everytwo weeks until progression or discontinuation of study drug due totoxicity.

DETAILED DESCRIPTION OF THE INVENTION

The use of picoplatin to treat metastatic colorectal cancer will beconducted in three parts. Phase 1 is a dose escalation study to identifythe maximum tolerated dose (MTD) of picoplatin that can be administeredeither every two weeks or every four weeks, with 5-FU and leucovorin(LV) administered every two weeks, as initial therapy for subjects withmetastatic colorectal cancer who have not been previously treated formetastatic disease. Phase 2 is a randomized study. In one arm of thestudy, picoplatin is tested at the MTD and selected schedule (every fourweeks) combined with 5-FU and leucovorin that are administered every twoweeks, to assess safety and efficacy. In the other arm, picoplatin willbe substituted for oxaliplatin in a modified FOLFOX 6 regimen whereinthe 100 mg/m² oxaliplatin dose in FOLFOX 6 has been reduced to 85 mg/m²,and administered every 2 weeks, so that the two agents can be comparedin the context of a widely used regimen. It is believed that cancerpatients can be more effectively treated with the regimen of the presentinvention, which employ picoplatin instead of cisplatin, carboplatin oroxaliplatin, because they will experience fewer side effects, such asneuropathy, while preferably receiving higher doses of the platinum (Pt)drug.

Subjects eligible for the Phase 1 study will have Stage 1V colorectalcancer and will have received no systemic therapy for metastatic cancer.Prior adjuvant chemotherapy with a 5-FU-based treatment regimen notcontaining oxaliplatin or irinotecan is acceptable if there has been atreatment-free interval of at least 6 months.

Phase 1

Subjects are assigned centrally to treatment with picoplatinadministered either every two or every four weeks and are assigned adose of picoplatin to be given dependent on the study results to date.Each patient also receives 5-FU and leucovorin therapy every two weeks.Cohorts of 3 subjects receive their assigned dose of picoplatin andleucovorin and 5-FU according to the following schedule:

Day 1: Picoplatin, assigned dosage, as a 2-hour infusion, given eitherevery cycle of 5-FU and leucovorin (q 2 weeks, Schedule A) or with everyother cycle of 5-FU and leucovorin (q 4 weeks, Schedule B). Leucovorin,400 mg/m² in D5W (water-5% dextrose), will be administered as a 2 hourinfusion, either alone or, if the patient is to receive picoplatin, atthe same time as picoplatin in separate bags using a Y-line. Theleucovorin (±picoplatin) will be followed by a 5-FU bolus=400 mg/m² andthen by 5-FU, 2,400 mg/m² in D5W administered as a 46 hour continuousinfusion.

Subjects in Phase 1 are centrally assigned to one of two schedules ofpicoplatin. The first cohort of q 2 week (Schedule A) subjects aretreated with picoplatin at a dosage of 45 mg/m², every cycle, q 2 weeks.Subsequent sequential cohorts of subjects assigned to this schedulereceive picoplatin at dose levels increasing by 15 mg/m² if treatment iswell tolerated and until unacceptable dose-limiting toxicity (DLT)establishes the MTD.

The MTD is defined as the dose of picoplatin below the dose at which atleast one third of at least 6 subjects experience a DLT. Tolerance datafrom only the first 4 weeks of treatment is used to determine the MTD.Thus, data following the first two doses of picoplatin in the q 2 week(Schedule A) subjects and following only the first dose of picoplatin inthe q 4 week (Schedule B) subjects are considered. The first cohort of q4 week (Schedule B) subjects will be treated with picoplatin at a dosageof 60 mg/m², every other cycle, q 4 weeks. Subsequent sequential cohortsof subjects assigned to this schedule will receive picoplatin at doselevels increasing by 30 mg/m² if treatment is well tolerated and untilunacceptable dose-limiting toxicity (DLT) establishes the MTD. Dependingon the pattern and severity of toxicity observed, additionalintermediate dose levels of either schedule of picoplatin administrationmay be studied.

Within each schedule, the cohort size is 3 subjects, and is expanded to6 subjects if a DLT is observed. Within each cohort of each schedule,one patient is treated initially; if no DLT is observed within thefollowing 4 weeks (2 drug cycles), the remaining two subjects may betreated. If a DLT is observed in the first patient within a cohort,whether or not to proceed with enrollment of additional subjects in thecohort will be determined on a case-by-case basis. All subjects within aq 2 week (Schedule A) cohort will have completed 2 cycles (a cycle=the2-day treatment regimen and an additional 12-day follow-up period) priorto escalating the dose in the next cohort of subjects. All subjectswithin a q 4 week (Schedule B) cohort will have completed 1 cycle of the2-day treatment regimen (which should include 5FU/leucovorin) and anadditional 26-day follow-up period prior to escalating the dose in thenext cohort of Schedule B subjects.

If no DLT is observed among the 3 subjects within a cohort, picoplatindose escalation may proceed in the next cohort of that schedule ofpicoplatin. If one DLT is observed, the cohort size at the specifieddose and schedule of picoplatin is expanded to 6 subjects. Additionalsubjects may be entered at any dosage level and schedule below the doseat which 2 of 6 have DLT to obtain additional safety or efficacy data.

Phase 2

The dose of the Phase 2 component of this study is selected based on thedose intensity of picoplatin achieved on each dose and schedule, thenumber of cycles tolerated and a subjective assessment of thetolerability and safety profile of each dose and schedule and apreliminary assessment of response rate in accord with Phase 1. Theschedule for Phase 2 is selected as Schedule B, the q 4 week schedule.The subjects (approximately 100 with metastatic CRC, at about 25clinical sites) are randomized to the modified FOLFOX 6⁶ or toFOLPI-150.

The FOLPI regimen is as follows:

Picoplatin 150 mg/m², is administered with every alternate cycle of 5-FUand leucovorin (q 4 weeks, Schedule B) as a 2 hour infusion. Leucovorin(400 mg/m² in D5W) is administered every 2 weeks as a 2-hour infusion,either alone, or given at the same time as the picoplatin in a separatebag using a Y-line. The administration of leucovorin±picoplatin isfollowed by a 5-FU bolus of 400 mg/m² and then by 5-FU, 2400 mg/m² inD5W administered as a 46 hour continuous infusion.

The modified FOLFOX 6 regimen is as follows:

Oxaliplatin 85 mg/m², as a 2-hour infusion is administered every 2weeks. Leucovorin (400 mg/m² in D5W) is administered every 2 weeks as a2-hour infusion. Oxaliplatin is given at the same time as the leucovorinin a separate bag using a Y-line. The administration ofleucovorin+oxaliplatin is followed by a 5-FU bolus of 400 mg/m² and thenby 5-FU, 2400 mg/m² in D5W administered as a 46 hour continuousinfusion.

Neuropathy assessment is performed at baseline and after every twocycles of therapy (approximately every month) by an independentneurologist. The subject and the neurologist are not informed whetherthe platinum infused is oxaliplatin or picoplatin. This assessment bythe neurologist is used to determine the incidence of Grade 2 or greaterperipheral neuropathy. In Phase 2, for the purpose of determiningtoxicity for dose reduction or study drug discontinuation, the treatingphysician performs a neurological assessment using the NCI CTCAE. TheseCTCAE criteria are used to determine the need to dose reduce prior toeach cycle. The assessment of the neurologist is used for determinationof the safety endpoint, the incidence of neuropathy, and is performedindependently every other cycle using the protocol-specified neuropathyscale, but is not be used for dose modification. For all subjects,hematology and serum chemistry laboratory studies are obtained prior toeach treatment cycle. Treatment cycles (5-FU and leucovorin±picoplatinor oxaliplatin depending on schedule) are repeated every 2 weeks, butmay be delayed up to 2 weeks while awaiting recovery of clinical orlaboratory abnormalities. Data from all cycles of treatment andcumulative toxicity are assessed for safety analysis.

Tumor evaluations will be done at baseline and after every 4th treatmentof 5-FU/leucovorin (every 8 weeks, unless doses have been delayed) onstudy. The efficacy endpoint will include objective response rateaccording to RECIST criteria.²⁶ Duration of response, time toprogression, progression-free survival, and overall survival are alsoevaluated.

The study treatments are summarized in FIGS. 1 and 2.

Selection of Picoplatin Dose

Picoplatin was generally tolerated in combination with othermyelosuppressive chemotherapeutic agents in previous Phase 1 studies atdoses of 120-150 mg/m² administered every 3 weeks, i.e., dosesequivalent to 80-100 mg/m² every 2 weeks or 160-200 mg/m² administeredevery 4 weeks. None of these studies, however, studied picoplatin incombination with 5-FU and leucovorin. 5-FU/leucovorin is not generallymyelotoxic and thus the doses of picoplatin selected as the initialstarting doses in the dose escalation portions of the current study,i.e., 45 mg/m² every two weeks and 60 mg/m² every four weeks, were wellbelow the expected MTDs of picoplatin administered on these schedules.

Administration of Picoplatin

Investigational-site staff must use standard cytotoxic handlingprocedures when preparing picoplatin for administration. Picoplatin issupplied as a ready-to-use formulation. The contents of the vials mustbe transferred to a suitable bag for administration. The compatibilityof the formulation with typical infusion equipment has been assessed,and results have established compatibility with EVA infusion bags, PVCinfusion tubing, and polypropylene syringes when the materials areprotected from light. PVC infusion bags are not recommended foradministration of picoplatin.

The compatibility of the formulation with typical administration setshas been assessed, and limits of acceptability have been set as 8 hoursin a covered infusion bag. The product is highly sensitive to light andshould not be exposed to ambient light for more than 1 hour withoutlight protection. The bag must be protected from light duringpreparation and administration at the time of use.

There is no preservative or bacteriostatic agent present in thepicoplatin formulation. Therefore, picoplatin must be transferred underaseptic conditions. The solution must be completely used or discardedwithin 8 hours of introduction into an infusion bag. As with allplatinum complexes, contact with aluminum should be avoided.

Picoplatin should be administered by peripheral vein or central line; itmust not be given by the intramuscular or subcutaneous route. Thestarting dose will be calculated based on the body surface area from theheight and weight of the patient. If the patient's weight changes bymore than 10%, the treating physician must recalculate the body surfacearea and amend the dose.

Picoplatin should be administered over 2 hours. It should beadministered concurrently with leucovorin, in separate bags using aY-line, when the two drugs are to be given on the same day. These twodrugs have been tested and shown to be compatible when administered inthis manner.

Subjects also received anti-emetic therapy consisting of a 5-HT₃receptor antagonist plus dexamethasone 30 minutes prior to a dose ofpicoplatin. Subjects may also receive anti-emetic therapy for severaldays following treatment, which may include oral lorazepam,prochlorperazine, or equivalent for up to 7 days, as clinicallyindicated for breakthrough nausea and/or vomiting.

Guidance for Administration

Detailed guidance for administration of 5-FU and leucovorin are providedin the product labels. Briefly, leucovorin 400 mg/m² IV infusion in D5Wwill be administered over 2 hours at the same time as picoplatin (ifpicoplatin is to be given on that day), in separate bags using a Y-line,followed by a bolus of 5-FU=400 mg/m² and then by 5-FU 2,400 mg/m² inD5W (recommended) administered as a 46-hour continuous IV infusion.

Dose Modifications

Dose Modification of Picoplatin

Dose-reduction is mandatory if any of the following hematological eventsare observed during the previous cycle: absolute neutrophil count(ANC)<0.5×10⁹/L for at least 5 days; absolute neutrophil count<1.0×10⁹/L complicated with Grade ≧2 fever (>38.5° C.); platelet count<25×10⁹/L; not reaching a platelet count ≧100×10⁹/L and ANC ≧1.5×10⁹/Lby Day 15.

Dose reduction is also required for any treatment events involving anytreatment-related Grade 3 toxicity, any Grade 4 toxicity, or any renaltoxicity or neurotoxicities as described below.

For subjects receiving picoplatin every 2 weeks, the dose reductionshould be 15 mg/m²; for subjects receiving picoplatin every 4 weeks thedose reduction should be 30 mg/m².

Dose Reduction in the Event of Serum Creatinine Changes

Serum creatinine must be measured before every dose of picoplatin. Forsubjects with abnormal serum creatinine, the dose of picoplatin (but not5-FU or leucovorin) must be modified according to the following table inPhase 1:

Dose modification for Dose modification for Serum Creatinine q 2 week(Schedule A) q 4 week (Schedule B) Value picoplatin subjects picoplatinsubjects ≦institutional ULN recommended dose recommended dose >1.0 to1.5 times reduce by 25% reduce by 25% ULN >1.5 to 2.0 times reduce by50% reduce by 50% ULN >2.0 times ULN discontinue treatment discontinuetreatment with picoplatin with picoplatin

In Phase 2, the following dose reductions will be required for elevatedserum creatinine:

Serum Dose modification for creatinine Phase 2 FOLPI subjects≦institutional ULN recommended dose >1.0 to 1.5 times ULN reduce bypicoplatin 30 mg/m² >1.5 to 2.0 times ULN reduce by picoplatin 60mg/m² >2.0 times ULN discontinue treatment with picoplatinDose Modification in the Event of Neurotoxicity

The dose of picoplatin should be modified according to the CTCAE gradeof toxicity and its duration as follows:

Duration of Toxicity Toxicity Resolves before Persistent (present atGrade next cycle start of next cycle) Grade 1 No change Maintainpicoplatin dose Grade 2 No change Reduce picoplatin dose by 30 mg/m²Grade 3 Reduce Discontinue picoplatin picoplatin dose by 30 mg/m² Grade4 Discontinue picoplatin

Up to three dose reductions of a 30 mg/m² may occur should toxicity notimprove or worsen at a later cycle.

Dose Modification of 5-FU

The first time the dose of picoplatin is reduced, the bolus dose of 5-FUshould be omitted. The second time the dose of picoplatin is reduced,the infusional dose should be reduced by 600 mg/m². Once decreased, thereduced dose of 5-FU should be continued; i.e., the dose of 5-FU shouldnot be subsequently increased.

If the platelet count or ANC count is Grade 1 or 2 at day 15 in a cyclewith picoplatin, and the subject receives the alternate i.e., evennumbered cycle that does not include picoplatin, the dose of 5-FU shouldnot be reduced at this cycle. At the next treatment cycle, the doses ofpicoplatin and 5-FU should be reduced by one level. Dose modificationsfor Grade 3 or 4 non-hematological events must be made. Continuetreatment only once toxicity has resolved to <Grade 3.

Dose Modification of Leucovorin

There are no dose modifications for leucovorin, unless drug sensitivityis suspected because of a temporal relationship to the time ofleucovorin administration.

Results

50 patients have been treated to date in Phase 1. In the q 2 w schedule,1 of 6 patients showed a DLT of Grade 4 thrombocytopenia and neutropeniaat a picoplatin dose level of 105 mg/m². The q 2 w schedule is now beingevaluated at 120 mg/m². In the q 4 w schedule, DLT was observed at 180mg/m² in 2 of 6 patients. Patients have received up to 24 cycles and thetherapy was well tolerated. For both schedules, dose delays wereprimarily from neutropenia or thrombocytopenia, with increasedhematological toxicity observed at higher doses. Grade 3non-hematological toxicities related to treatment include 1 coronaryartery spasm following FU infusion, 1 picoplatin infusional allergicreaction, 1 stomatitis, 2 diarrhea, 1 azotemia. The cardiac andstomatitis events were attributed to the 5-FU component. No Grade 2 orhigher neuropathy has been reported, even for four patients who havereceived a cumulative picoplatin dose of greater than about 900 mg/m², asurprising and unexpected result, particularly in view of a highincidence of moderate to severe neuropathy observed at comparable dosesof oxaliplatin. Picoplatin can be safely administered with FU and LVwithout the dose limiting neuropathy associated with FOLFOX.

In Schedule A (picoplatin q 2 week), the preferred dosage range is about45-120 mg/m², e.g., doses of 45 to 105 mg/m², e.g., 45 mg/m².

In Schedule B (picoplatin q 4 week), the preferred dose can be higher,e.g., about 120-210 mg/m², e.g., 120-180 mg/m², e.g., 150 mg/m². A lowerdose can also be administered, e.g., at 45-90 mg/m², e.g., 60 mg/m².

Of 44 evaluated subjects evaluated by CT scan there have been 6confirmed partial responses and one complete response (unconfirmed)(16%). Twenty-six of 32 subjects of the Q2 week schedule have beenevaluated and 2 partial responses were observed. Surprisingly, ⅔patients in cohort A1 (45 mg/m²) showed a partial response. Eighteen of18 subjects in the Q4 week schedule have been evaluated and 5 partialresponses were observed (28%).

REFERENCES

The following references and other publications, patents and patentapplications cited herein are incorporated by reference herein.

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1. A method of treatment of colorectal cancer, comprising: administeringto a patient afflicted with metastatic colorectal cancer picoplatin,5-fluorouracil (5-FU), and leucovorin, wherein 5-FU and leucovorin areadministered intravenously at least twice at intervals of about 2 weeksand the picoplatin is administered at doses of about 60-180 mg/m² everyother time that the fluorouracil and leucovorin are administered.
 2. Themethod of claim 1 wherein the patient has not previously been treatedfor metastatic colorectal cancer.
 3. The method of claim 1 wherein thepicoplatin and the leucovorin are administered substantiallyconcurrently.
 4. The method of claim 3 wherein the picoplatin and theleucovorin are administered simultaneously.
 5. The method of any one ofclaims 1, 3 or 4 wherein the 5-FU is administered following theadministration of the picoplatin and the leucovorin.
 6. The method ofclaim 5 wherein the leucovorin is administered at a dosage of about 400mg/m².
 7. The method of claim 5 wherein the 5-FU is administered at atotal dosage per dosing of about 2000-3000 mg/m².
 8. The method of claim7 wherein the picoplatin is administered at a dosage of about 120-180mg/m².
 9. The method of claim 8 wherein a subsequent dose of picoplatinis administered at about a 15-30 mg/m² lower dose than a previous dose.10. The method of claim 9 wherein the picoplatin is administered atleast once at a dosage of about 150 mg/m².
 11. The method of claim 1,wherein a cumulative dose of greater than about 900 mg/m² of picoplatinis delivered to the patient.
 12. The method of claim 1 wherein theleucovorin, at a dosage of about 400 mg/m², is administered as a 2 hourinfusion, the administration of the leucovorin being followed by a 5-FUbolus at a dosage of about 400 mg/m²; the 5-FU bolus being followed by5-FU at a dosage of about 2,400 mg/m² administered as a 46 hourcontinuous infusion; wherein the leucovorin and the 5-FU areadministered to the patient every 2 weeks and about 60-150 mg/m² of thepicoplatin is administered to the patient with the leucovorin and the5-FU every 4 weeks, wherein at least the initial dose of picoplatin isabout 150 mg/m².
 13. The method of claim 1 wherein the leucovorin isadministered at a dose of about 250-500 mg/m², being followed by a doseof about 2,000-3,000 mg/m² 5-FU; wherein the leucovorin and the 5-FU areadministered to the patient every two weeks and about 120-150 mg/m² ofthe picoplatin is administered to the patient with the leucovorin andthe 5-FU every 4 weeks.
 14. The method of any one of claims 1, 12 or 13comprising administering the picoplatin in a dosage form comprising anisotonic solution comprising: (a) water; (b) a tonicity adjuster; and(c) about 0.5 mg/mL dissolved picoplatin.